Published on Web 02/11/2006
Total Synthesis of FR901464, an Antitumor Agent that Regulates the Transcription of Oncogenes and Tumor Suppressor Genes Brian J. Albert, Ananthapadmanabhan Sivaramakrishnan, Tadaatsu Naka, and Kazunori Koide* Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue, Pittsburgh, PennsylVania 15260 Received December 2, 2005; E-mail:
[email protected] In search for anticancer natural products with new modes of action, the Fujisawa group isolated FR901464 (Scheme 1) from the culture broth of a bacterium of Pseudomonas sp. No.2663 as a novel transcriptional activator.1 This natural product lowers the mRNA levels of p53, p21, c-myc, and E2F-1 in MCF-7 cells at 20 nM1b and induces apparent apoptosis in MCF-7 cells with the impressive LC50 of 0.5 nM. It also exhibits an antitumor activity in a mouse model at remarkably low concentrations (0.056-0.18 mg/kg).1b This unprecedented pharmacological profile of FR901464 has drawn considerable interest2 and prompted us to further investigate the biology of FR901464. Despite the two previous syntheses of FR901464,3 a more concise synthetic approach was highly desirable to take full advantage of such biological activities. Scheme 1 illustrates our retrosynthetic analysis of FR901464, in which the priority was to accomplish a coupling between A- and B-ring fragments with complete functionality for ultimate convergency. While several intramolecular diene-ene olefin metathesis reactions have been reported,4 the corresponding intermolecular version was unprecedented in natural product synthesis at the outset of this research.5 Nonetheless, we reasoned that the ruthenium-alkylidene complex with 2 would be more reactive than that of 1 (if the terminal olefin reacts), the trisubstituted and electron-deficient olefin would not react with the ruthenium catalyst due to steric and electronic reasons, and thermodynamics would favor FR901464 over the homodimer of 2 under reversible conditions. Further retrosynthetic analysis of the A-ring fragment 1 and B-ring fragment 2 revealed acid 3, amine 4, and selenide 5. With this strategy in mind, carboxylic acid 3 was prepared as shown in Scheme 2. We chose to use the styrene unit as a masked aldehyde because the styryl group significantly suppressed the volatility of otherwise low molecular weight intermediates. Known enyne 6 was prepared from cinnamaldehyde according to the literature (TMSCHN2, LDA, 84%).6 The next step employed a Carreira asymmetric alkynylation between 6 and acetaldehyde to generate alcohol 7.7 This alcohol was then converted to acetate 8, and subsequent ozonolysis afforded aldehyde 9. Further oxidation of this aldehyde gave 10, which was then partially hydrogenated with Lindlar’s catalyst to afford 3. Scheme 3 outlines the preparation of 1. The L-threonine derivative 11, prepared in one step (2-methoxypropene, CSA; quant.) from commercially available N-Boc-L-threonine methyl ester, was transformed to 12 using a one-pot procedure (DIBALH; Ph3PdCH2).8 Removal of the oxazolidine ring of 12 using CSA in MeOH generated alcohol 13, and subsequent O-methallylation afforded diene 14. The ring-closing metathesis of 14 was quantitative using 1 mol % of Grubbs’ 2nd generation catalyst9 to provide 15. To prepare lactone 16, we found that allylic oxidation of 15 with PDC was most regioselective and efficient. Subsequent stereoselective hydrogenation of 16 gave desired lactone 17 and its C12-epimer in a 10:1 ratio. The allylation of 17 gave hemiketal 2792
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Scheme 1. Retrosynthetic Analysis of FR901464
Scheme 2. Preparation of 3a
a Conditions: (a) CH CHO (2.3 equiv), Zn(OTf) (1.0 equiv), Et N (1.0 3 2 3 equiv), (-)-N-methylephedrine (1.0 equiv), toluene, 23 °C, 41% (72% ee); (b) Ac2O (5.0 equiv), pyridine, 23 °C, quant.; (c) O3, CH2Cl2, -78 °C; Me2S (10 equiv), -78f23 °C, 89%; (d) NaClO2 (3.0 equiv), NaH2PO4 (3.0 equiv), 2-methyl-2-butene (15 equiv), H2O/tBuOH (1:1), 23 °C; (e) H2 (1 atm), Lindlar’s catalyst (1 mol %), quinoline (10 mol %), EtOH, 23 °C, 75% (2 steps).
18, which is in equilibrium with an aminal. Due to the presence of two anomers for both 18 and the aminal, we were not able to determine the relative ratio among these four compounds. In the next step, this mixture was subjected to reduction conditions (BF3‚OEt2, Et3SiH, CF3CH2OH), providing the desired compound 19 along with a pyrrolidine derivative (see Supporting Information). Subsequent coupling of 3 and 19 (via amine 4) gave amide 20. Methacrolein and 20 were then subjected to the cross-olefin metathesis conditions using 5 mol % of catalyst 2210 to form the desired aldehyde 21, which was then converted to diene 1 upon addition of Ph3PdCH2. B-ring fragment 2 was prepared according to Scheme 4. Through the three-step sequence that we previously reported, aldehyde 23 was prepared from methallyl bromide and propargyl alcohol.11 The subsequent C4-C5 bond formation was most stereoselective and efficient using the Zr/Ag-promoted alkynylation method developed in our laboratory to afford 24 and C4-epimer in a ratio of 6:1 in favor of 24.12 While the partial hydrogenation of 24 or its TES ether failed, the Red-Al reduction protocol from our laboratory successfully afforded allylic alcohol 25.13 This alcohol was protected as the TES ether 26, which was then reduced by DIBAL-H to furnish the primary alcohol 27. Transformation of the hydroxy group of 27 to the o-nitrophenylselenide gave 5. Despite the lack of closely related Mislow-Evans-type [2,3]-sigmatropic rearrangements of 10.1021/ja058216u CCC: $33.50 © 2006 American Chemical Society
COMMUNICATIONS Scheme 3. Preparation of 1a
a Conditions: (a) DIBAL-H (2.0 equiv), CH Cl , -78 °C; Ph PCH Br 2 2 3 3 (2.1 equiv), tBuOK (2.0 equiv), THF, -78f48 °C, 77%; (b) CSA (10 mol %), MeOH, 23 °C, 95%; (c) methallyl bromide (4.0 equiv), Ag2O (1.5 equiv), DMF, 23 °C, 86%; (d) Grubbs’ 2nd cat. (1 mol %), PhH, reflux, quant.; (e) PDC (6.0 equiv), (ClCH2)2, reflux, 72%; (f) H2 (1 atm), PtO2 (1 mol %), EtOH, 23 °C; quant.; (g) allyl-MgBr (2.0 equiv), THF, -78 °C, 96%; (h) Et3SiH (10 equiv), BF3‚OEt2 (4.0 equiv), CF3CH2OH (8.0 equiv), -78 °C, 38%; (i) TFA/CH2Cl2 (1:9), 23 °C, 3 (1.2 equiv), HATU (1.2 equiv), iPr2NEt (4.0 equiv), 23 °C, 86%; (j) 22 (5 mol %), methacrolein (20 equiv), CH2Cl2, 23 °C, 57% (67% based on recovered 20); (k) Ph3PCH3Br (1.4 equiv), tBuOK (1.2 equiv), THF, 0 °C, 86%.
Scheme 4. Preparation of 2a
Scheme 5. Final Stage
raphy3a partly accounts for the loss of the material. Only 5% of homodimers of 2 were detected, and diene 1 did not form its homodimer under the reaction conditions. The fragile nature of 2 (thermal decomposition at g47 °C) precluded more forcing reaction conditions. In summary, we completed the total synthesis of FR901464 in the 13 longest linear steps with 31 total steps, which features Zr/ Ag-promoted alkynylation using electron-deficient methyl propiolate, mild Red-Al reduction, stereoselective [2,3]-sigmatropic rearrangement via a selenoxide, and diene-ene cross olefin metathesis without protecting groups. Biological studies of FR901464 and its analogs are underway in our laboratory. Acknowledgment. We wish to dedicate this paper to the 60th birthday of Professor K. C. Nicolaou. This work was supported by the University of Pittsburgh, the American Chemical Society (PRF No. 38542-G1), The American Cancer Society George Heckman Institutional Research Grant, and The Competitive Medical Research Fund. B.J.A. is thankful for a Graduate Excellence Fellowship. Supporting Information Available: Experimental procedures and spectroscopic data for all the new compounds and FR901464. This material is available free of charge via the Internet at http://pubs.acs.org. References
a Conditions: (a) Ag-CtC-CO Me (1.7 equiv), Cp ZrCl (1.3 equiv), 2 2 2 AgOTf (0.2 equiv), CH2Cl2, 23 °C, 84%; (b) Red-Al (2.0 equiv), -72 °C, 81%; (c) TESCl (1.4 equiv), imidazole (1.5 equiv), THF, 0 °C, quant.; (d) DIBAL-H (3.0 equiv), THF, -78 °C, 95%; (e) o-O2N-PhSeCN (1.2 equiv), nBu P (1.4 equiv), THF, 0 °C, quant.; (f) H O (30% v/v in H O, excess), 3 2 2 2 DMAP (5.0 equiv), THF, -44f23 °C, 96%; (g) TESCl (1.4 equiv), imidazole (1.6 equiv), THF, 0 °C, 95%; (h) OsO4 (1 mol %), NMO (0.96 equiv), THF/H2O (10:1), 0f23 °C; Pb(OAc)4 (1.2 equiv), PhH, 0f23 °C, 71% (86% based on recovered 29); (i) AcOH/THF/H2O (3:3:1), 0f23 °C, 91%.
chiral E-allylselenides, we proceeded to treat substrate 5 with H2O2 and DMAP, which promoted a rearrangement via the putative selenoxide to provide the desired allylic alcohol 28 and its diastereomer with a pleasantly surprising diastereomeric ratio of 7.5:1.14 Alcohol 28 was protected as the TES ether 29, which dramatically improved the regioselectivity of the oxidative cleavage sequence (OsO4-NMO; Pb(OAc)4), giving ketone 30. Finally, both TES groups were hydrolyzed under carefully optimized conditions to form the fully functionalized B-ring fragment 2. The stage was set to test the cross diene-ene metathesis between 1 and 2 (Scheme 5). Gratifyingly, despite the absence of protecting groups, the coupling of these two fragments in the presence of catalyst 22 furnished FR901464 in 40% yield after subjecting the unreacted 1 and 2 to the same conditions without a detectable cis isomer. The decomposition of FR901464 during column chromatog-
(1) (a) Nakajima, H.; Sato, B.; Fujita, T.; Takase, S.; Terano, H.; Okuhara, M. J. Antibiot. 1996, 49, 1196-1203. (b) Nakajima, H.; Hori, Y.; Terano, H.; Okuhara, M.; Manda, T.; Matsumoto, S.; Shimomura, K. J. Antibiot. 1996, 49, 1204-1211. (c) Nakajima, H.; Takase, S.; Terano, H.; Tanaka, H. J. Antibiot. 1997, 50, 96-99. (2) A few examples: (a) Imamura, Y.; Ohtsu, Y.; Tanaka, H.; Hatakeyama, M.; Manabe, T.; Kawaguchi, H.; Handa, H.; Takahashi, T. Heterocycles 2004, 64, 51-56. (b) Tashiro, E.; Imoto, M.; Yoshida, M.; Kitahara, T.; Watanabe, H.; Nakajima, H. Jpn. Kokai Tokkyo Koho JP 2005323514, Nov. 24, 2005. (3) (a) Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 9974-9983; 40 total, 20 longest linear steps. (b) Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T. Tetrahedron Lett. 2001, 42, 8207-8210; 42 total, 24 longest linear steps. (4) For examples, see: (a) Yang, Z. Q.; Geng, X. D.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 78817889. (b) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569-572. (c) Clive, D. L. J.; Liu, D. Z. Tetrahedron Lett. 2005, 46, 5305-5307. (5) Presentation of preliminary results: (a) Albert, B. J.; Sivaramakrishnan, A.; Koide, K. 228th ACS National Meeting, Philadelphia, PA, Aug 2226; American Chemical Society: Washington, DC, 2004. First appearance in the literature: (b) Crimmins, M. T.; Christie, H. S.; Chaudary, K.; Long, A. J. Am. Chem. Soc. 2005, 127, 13810-13812. (6) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107-108. (7) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806-1807. (b) The catalytic version was unsuccessful. (c) Alcohol 7 was recrystallized to 95% ee and used in subsequent steps. (8) Wei, Z.-Y.; Knaus, E. E. Synthesis 1994, 1463-1466. (9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953956. (10) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed. 2002, 41, 4038-4040. (11) Albert, B. J.; Koide, K. Org. Lett. 2004, 6, 3655-3658. (12) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525-2527. (13) Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785-1787. (14) (a) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 71547155. (b) Reich, H. J. J. Org. Chem. 1975, 40, 2570-2572.
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